The present invention relates to a cartilage regeneration and repair product that induces cell ingrowth into a bioresorbable material and cell differentiation into cartilage tissue, and to methods of using such a product to repair cartilage lesions.
Articular cartilage, an avascular tissue found at the ends of articulating bones, has limited natural capacity to heal. During normal cartilage ontogeny, mesenchymal stem cells condense to form areas of high density and proceed through a series of developmental stages that ends in the mature chondrocyte. The final hyaline cartilage tissue contains only chondrocytes that are surrounded by a matrix composed of type II collagen, sulfated proteoglycans, and additional proteins. The matrix is heterogenous in structure and consists of three morphologically distinct zones: superficial, intermediate, and deep. Zones differ among collagen and proteoglycan distribution, calcification, orientation of collagen fibrils, and the positioning and alignment of chondrocytes (Archer et al., 1996, J. Anat. 189(1):23-35; Morrison et al., 1996, J. Anat. 189(1): 9-22; and Mow et al., 1992, Biomaterials 13(2): 67-97). These properties provide the unique mechanical and physical parameters to hyaline cartilage tissue.
The meniscus, a C-shaped cartilaginous tissue, performs several functions in the knee including load transmission from the femur to the tibia, stabilization in the anterior-posterior position during flexion, and joint lubrication. Damage to the meniscus results in reduced knee stability and knee locking. Over 20 years ago, meniscectomies were performed which permitted immediate pain relief, but were subsequently found to induce the early onset of osteoarthritis (Fairbank, J. Bone Joint Surg. 30B: 664-670; Allen et al., 1984, J. Bone Joint Surg. 66B:666-671; and Roos et al., 1998, Arth. Rheum. 41:687-693). More recently, partial meniscectomies and repair of meniscal tears have been performed (FIGS. 9A-D; Jackson, D., ed., 1995, Reconstructive Knee Surgery Master Techniques in Orthopedic Surgery, ed. R. Thompson, Raven Press: New York). However, partial resection results in the loss of functional meniscus tissue and the early onset of osteoarthritis (Lynch et al., 1983, Clin. Orthop. 172:148-153; Cox et al., 1975, Clin. Orthop. 109:178-183; King, 1995, J. Bone Joint Surg. 77B:836-837). Additionally, repair of meniscal tears is limited to tears in the vascular ⅓ of the meniscus; tears in the semivascular to avascular ⅔ are not repairable (FIGS. 9A-D; Jackson, ibid.). Of the approximately, 560,000 meniscal injuries that occur annually in the United States, an estimated 80% of tears are located in the avascular, irreparable zone. Clearly, a method that both repairs xe2x80x9cnon-repairablexe2x80x9d tears or that can induce regeneration of resected menisci would be valuable for painless musculoskeletal movement and prevention of the early onset of osteoarthritis in a large segment of the population.
The proximal, concave surface of the meniscus contacts the femoral condyle and the distal, flat surface contacts the tibial plateaus. The outer one-third of the meniscus is highly vascularized and contains dense, enervated, connective tissue. In contrast, the remaining meniscus is semivascular or avascular, aneural tissue consisting of fibrochondrocytes surrounded by abundant extracellular matrix (McDevitt et al., Clin. Orthop. Rel. Res. 252:8-17). Fibrochondrocytes are distinctive in both appearance and function compared to undifferentiated fibroblasts. Fibroblasts are elongated cells containing many cellular processes and produce predominantly type I collagen. The matrix produced by fibroblasts does not produce a sufficient mechanical load. In contrast, fibrochondrocytes produce type I and type II collagen and proteoglycans. These matrix components support compressive forces that are commonly exerted on the meniscus during musculoskeletal movement.
In the 1960""s, demineralized bone matrix was observed to induce the formation of new cartilage and bone when implanted in ectopic sites (Urist, 1965, Science 150:893-899). The components responsible for the osteoinductive activities were termed Bone Morphogenetic Proteins (BMP). At least seven individual BMP proteins were subsequently identified from bone (BMP 1-7) and amino acid analysis revealed that six of the seven BMPs were related to each other and to other members of the TGF-xcex2 superfamily. During endochondral bone formation, TGF-xcex2 family members direct a cascade of events that includes chemotaxis, differentiation of pluripotential cells to the cartilage lineage, maturation of chondrocytes to the hypertrophic stage, mineralization of cartilage, replacement of cartilage with bone cells, and the formation of a calcified matrix (Reddi, 1997, Cytokine and Growth Factor Reviews 8:11-20). Although individual, recombinant BMPs can induce these events, the prevalence of multiple TGF-xcex2 family members in bone tissue underlies the complexity involved in natural osteogenesis.
Bone Protein (Sulzer Orthopedics Biologics, Wheatridge, Colo.), also referred to herein as BP, is a naturally derived mixture of proteins isolated from demineralized bovine bones that has osteogenic activity in vitro and in vivo. In the rodent ectopic model, BP induces endochondral bone formation or bone formation through a cartilage intermediate (Damien, C. et al., 1990, J. Biomed. Mater. Res. 24:639-654). BP in combination with calcium carbonate promotes bone formation in the body (Poser and Benedict, PCT Publication No. WO95/13767). In vitro, BP has been shown to promote differentiation to cartilage of murine embryonic mesenchymal stem cells (Atkinson et al., 1996, In xe2x80x9cMolecular and Developmental Biology of Cartilagexe2x80x9d, Bethesda, Md., Annals New York Acad. Sci. 785:206-208; Atkinson et al., 1997, J. Cell. Biochem. 65:325-339) and of adult myoblast and dermal cells (Atkinson et al., 1998, 44th Annual Meeting, Orthopaedic Research Society, abstract). To ensure chondrogenesis in these in vitro systems, however, culture conditions must be tightly controlled throughout the culture period, including by controlling cellular organization within the culture, optimizing media formulations, and adding exogenous factors that must be carefully established to maximize chondrogenesis over mitogenesis. Such optimization of conditions makes the application of the disclosed in vitro methods to an in vivo system unrealistic and unpredictable. In addition, although in vitro cultures of adult myoblast and dermal cells initially resulted in chondrogenesis, the effect was only transient and over time, the cultures reverted to their original phenotype. Although certain embryonic and precursor cell types showed prolonged chrondrogenesis in vitro in these studies, it would be unpredictable or even impossible in the case of embryonic cells that these specific cell types could be recruited to a site in vivo in an adult patient.
Atkinson et al., in PCT Application No. PCT/EP/05100, incorporated herein by reference in its entirety, describe a delivery system for osteoinductive and/or chondroinductive mixture of naturally derived factors for the induction of cartilage repair.
Hunziker (U.S. Pat. Nos. 5,368,858 and 5,206,023) describes a cartilage repair composition consisting of a biodegradable matrix, a proliferation and/or chemotactic agent, and a transforming factor. A two-stage approach is used where each component has a specific function over time. First, a specific concentration of proliferation/chemotactic agent fills the defect with repair cells. Second, a larger transforming factor concentration, preferably provided in conjunction with a delivery system, transforms repair cells to chondrocytes. The second stage delivery of a high concentration of transforming factor in a delivery system (i.e., liposomes) was required to obtain formation of hyaline cartilage tissue at the treatment site.
Chen and Jeffries (U.S. Pat. No. 5,707,962) describe osteogenic compositions consisting of collagen and sorbed factors to enhance osteogenesis.
Valee and King (U.S. Pat. No. 4,952,404) describe healing of injured, avascular meniscus tissue by release of the angiogenic factor, angiogenin, over at least 3 weeks.
Previously, Amoczky et al. described a method using an autogenous fibrin clot to repair an avascular, circular lesion in canine menisci (Amoczky et al., 1988, J. Bone Joint Surg. 70A:1209-1217). This approach enhanced repair of meniscal tissue compared to controls lacking the fibrin clot. However, the repair tissue was not meniscus-like tissue, but rather connective scar tissue.
Hashimoto et al. described a method using fibrin sealant with or without endothelial cell growth factor in avascular, circular meniscal defects in the canine model (Hashimoto et al., 1992, Am. J. Sports Med. 20:537-541). The growth factor added a modest benefit compared to healing with fibrin sealant alone and this additional effect was not observed until three months after treatment, indicating an indirect contribution of the growth factor. In addition, the defect was filled with hyaline cartilage-like cells, which are not typically present in normal meniscus tissue.
Shirakura, et al. describe the use of an autogenous synovium graft sutured into meniscal tears. While the synovium did enhance healing in ⅓ of the animals, the grafts healed with fibrous tissue, not fibrocartilaginous tissue normally observed in meniscus tissue (Shirakura, 1997, Acta. Orthop. Scand. 68:51-54). Furthermore, ⅔ of the grafts did not heal.
The molecular mechanism for cartilage and bone formation has been partially elucidated. Both bone morphogenetic proteins (BMP) and transforming growth factor xcex2 (TGFxcex2) molecules bind to cell surface receptors (i.e., TGFxcex2/BMP receptors) to initiate a cascade of signals to the nucleus that promotes proliferation, differentiation to cartilage, and/or differentiation to bone (Massague, 1996, Cell 85:947-950). In 1984, Urist described a substantially pure, but not recombinant, BMP combined with a biodegradable poly(lactic acid) polymer delivery system for bone repair (U.S. Pat. No. 4,563,489). This system blends together equal quantities of BMP and poly(lactic acid) (PLA) powder (100 xcexcg of each) and decreases the amount of BMP required to promote bone repair.
Hattersley et al. (WO 96/39170) disclose a two factor composition for inducing cartilaginous tissue formation using a cartilage formation-inducing protein and a cartilage maintenance-inducing protein. Specific recombinant cartilage inducing proteins are specified as BMP-13, MP-52 and BMP-12, and specific cartilage maintenance-inducing proteins are specified as BMP-9. In one embodiment, BMP-9 is encapsulated in a resorbable polymer system and delivered to coincide with the presence of cartilage formation inducing protein(s).
Laurencin et al. (U.S. Pat. No. 5,629,009) disclose a chondrogenesis-inducing device, consisting of apolyanhydride and polyorthoester, that delivers water soluble proteins derived from demineralized bone matrix, TGFxcex2, epidermal growth factor (EGF), fibroblast growth factor (FGF) or platelet-derived growth factor (PDGF).
Bentz et al. (PCT Publication No. WO 92/09697) have described the use of a bone morphogenetic protein (BMP) with a TGFxcex2 protein for bone repair. The ratio of BMP to TGFxcex2 in the mixture is in the range of 10:1 to 1:10. The addition of TGF-xcex2 with either BMP-2 or BMP-3 results in increased osteoinductive activity and an increased ratio of cartilage to bone when compared to either factor alone (Bentz et al., Matrix 11:269-275 (1991); Ogawa et al., J. Biol. Chem., 267(20): 14233-7 (1992); WO92/09697). However, this composition produced substantial bone in the rodent subcutaneous assay.
Bulpitt and Aeschlimann found that TGFxcex2-2 and BMP-2 led to accelerated bone formation and decreased cartilage formation in the rat ectopic bone formation assay (Bulpitt et al., Tissue Engineering, pp. 162-169 (1999)).
Other studies demonstrate no or little effect of the combination of TGFxcex2-1 or -2 with BMP. In vitro, the combination of TGFxcex2-1 and porcine BMP demonstrated no synergistic effects on collagen production (Kim et al., Biochem. Mol. Biol. Int""l, 33(2):253-261 (1994)). Similarly, Ballock et al., demonstrated no synergy between TGFxcex2-1 and BMP-3 for collagen production in periosteum derived cells in vitro (Ballock et al., J. Ortho. Res., 15:463-7 (1997)).
In the Rosen modified Sampath-Reddi rodent assay (Sampath et al., Proc. Nat""l Acad. Sci. USA, 80(21):6591-5 (1983)), BMP-2 containing implants showed cartilage and bone formation after ten days and mostly bone (no cartilage) after 21 days (U.S. Pat. No. 5,658,882).
Previously, Li and Stone (U.S. Pat. No. 5,681,353) have described a Meniscal Augmentation Device that consists of biocompatible and bioresorbable fibers that acts as a scaffold for the ingrowth of meniscal fibrochondrocytes, supports normal meniscal loads, and has an outer surface that approximates the natural meniscus contour. After partial resection of the meniscus to the vascular zone, this device is implanted into the resulting segmental defect. The results have been described in both canines and humans (Stone et al., 1992, Am. J. Sports Med. 20:104-111; and Stone et al., 1997, J. Bone Joint Surg. 79:1770-1777).
The Meniscus Augmentation Device, the research reports and patent disclosures described above, and current repair surgeries provide encouraging results in the area of cartilage repair, but are not satisfactory to induce repair of xe2x80x9cnon-repairablexe2x80x9d avascular tears in which the repair tissue is meniscus tissue, and are not satisfactory to produce short patient rehabilitation times and regenerated meniscus tissue in the vascular zone. Furthermore, no reports have been described that demonstrate enhanced healing rates of xe2x80x9crepairablexe2x80x9d meniscal tears in vivo.
The present invention relates to a product and method for repairing and/or regenerating cartilage lesions. The product and method of the present invention are useful for repairing a variety of cartilage lesions, including articular and mensical lesions, including vascular, semivascular and avascular lesions. Moreover, the product and method of the present invention can be used to repair different sizes and shapes of cartilage lesions, including radial tears, bucket handle tears, and segmental defects.
A first embodiment of the product of the present invention relates to a product for repair of cartilage lesions. Such a product includes: (a) a cartilage repair matrix; and, (b) a cartilage-inducing composition associated with the matrix for provision of a mixture of proteins. In one embodiment of the product of the present invention, a cartilage-inducing composition includes a mixture of proteins which includes: transforming growth factor xcex21 (TGFxcex21), bone morphogenetic protein (BMP)-2, BMP-3, and BMP-7. The quantity of the TGFxcex21 in the mixture is from about 0.01% to about 99.99% of total proteins in the mixture; the quantity of the BMP-2 in the mixture is from about 0.01% to about 10% of total proteins in the mixture; the quantity of the BMP-3 in the mixture is from about 0.1% to about 15% of total proteins in the mixture; and, the quantity of the BMP-7 in the mixture is from about 0.01% to about 10% of total proteins in the mixture.
In a second embodiment of the product of the present invention, a cartilage-inducing composition includes a mixture of proteins which includes (a) a bone-derived osteogenic or chondrogenic formulation; and, (b) an exogenous TGFxcex2 protein. The exogenous TGFxcex2 protein is present in an amount sufficient to increase cartilage induction by the composition over a level of cartilage induction by the bone-derived osteogenic or chondrogenic protein formulation in the absence of the exogenous TGFxcex2 protein. In one aspect of this embodiment, the exogenous TGFxcex2 protein is TGFxcex21. In this aspect, the ratio of TGFxcex21 to all other proteins in the mixture of proteins is at least about 1:10, at least about 1:3, at least about 1:1, or at least about 10:1.
In a third embodiment of the product of the present invention, a cartilage-inducing composition includes a mixture of proteins comprising: (a) a TGFxcex2 protein; and, (b) at least one bone morphogenetic protein (BMP), wherein the ratio of the TGFxcex2 protein to the BMP protein is greater than about 10:1. In this embodiment, the TGFxcex2 protein can be any TGFxcex2 protein, including TGFxcex21, TGFxcex22, TGFxcex23, TGFxcex24, TGFxcex25, or mixtures thereof. In a preferred embodiment, the TGFxcex2 protein is TGFxcex21 or TGFxcex22, with TGFxcex21 being most preferred. The BMP protein can be any BMP protein, including, but not limited to, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9, CDMP, and mixtures thereof.
In one aspect of the any of the above-described embodiments of the present invention, the mixture of proteins includes TGFxcex2 superfamily proteins: TGFxcex21, bone morphogenetic protein (BMP)-2, BMP-3, and BMP-7, wherein the TGFxcex2 superfamily proteins comprise from about 0.5% to about 99.99% of the mixture of proteins. In one aspect, the TGFxcex2 superfamily proteins comprise from about 0.5% to about 25% of the mixture of proteins; in another aspect, the TGFxcex2 superfamily proteins comprise from about 1% to about 10% of the mixture of proteins.
In one aspect of each of the above-referenced embodiments, the quantity of the TGFxcex21 in the mixture is from about 0.01% to about 75% of total proteins in the mixture; in another aspect, the quantity of the TGFxcex21 in the mixture is from about 0.01% to about 50% of total proteins in the mixture; in another aspect, the quantity of the TGFxcex21 in the mixture is from about 0.01% to about 25% of total proteins in the mixture; in another aspect, the quantity of the TGFxcex21 in the mixture is from about 0.01% to about 10% of total proteins in the mixture; in another aspect, the quantity of the TGFxcex21 in the mixture is from about 0.1% to about 1% of total proteins in the mixture; in another aspect, the quantity of the TGFxcex21 in the mixture is from about 33% to about 99.99% of total proteins in the mixture; in another aspect, the quantity of the TGFxcex21 in the mixture is from about 50% to about 99.99% of total proteins in the mixture.
In one aspect of each of the above-referenced embodiments, the quantity of the BMP-2 in the mixture is from about 0.1% to about 5% of total proteins in the mixture. In one aspect of each of the above-referenced embodiments, the quantity of the BMP-3 in the mixture is from about 0.1% to about 5% of total proteins in the mixture. In one aspect of each of the above-referenced embodiments, the quantity of the BMP-7 in the mixture is from about 0.1% to about 5% of total proteins in the mixture. In the first embodiment of the product of the present invention, the quantity of BMP-3 in the mixture is from about 0.1% to about 10% of total proteins in the mixture.
In one aspect of each of the above-referenced embodiments, the mixture of proteins further comprises a protein selected from the group consisting of TGFxcex22, TGFxcex23, BMP-4, BMP-5, BMP-6, BMP-8, BMP-9, and cartilage-derived morphogenetic protein (CDMP). In one aspect, the TGFxcex22 comprises from about 0.5% to about 12% of the mixture of proteins; in another aspect, the TGFxcex23 comprises from about 0.01% to about 15% of the mixture of proteins; in another aspect, the BMP-4 comprises from about 0.01% to about 1% of the mixture of proteins; in another aspect, the BMP-5 comprises from about 0.01% to about 1% of the mixture of proteins; in another aspect, the BMP-6 comprises from about 0.01% to about 1% of the mixture of proteins; in another aspect, the CDMP comprises from about 0.01% to about 1% of the mixture of proteins.
In another aspect of each of the above-referenced embodiments, the mixture of proteins further comprises at least one bone matrix protein. The bone matrix protein can include, but is not limited to, osteocalcin, osteonectin, bone sialoprotein (BSP), lysyloxidase, cathepsin L pre, osteopontin, matrix GLA protein (MGP), biglycan, decorin, proteoglycanchondroitin sulfate III (PG-CS III), bone acidic glycoprotein (BAG-75), thrombospondin (TSP) and fibronectin. Typically, the bone matrix protein comprises from about 20% to about 98% of the mixture of proteins. In one aspect, the bone matrix proteins comprise: osteocalcin, osteonectin, bone sialoprotein (BSP), lysyloxidase, and cathepsin L pre. In another aspect, the bone matrix protein comprises from about 40% to about 98% of the mixture of proteins.
In another aspect of each of the above-referenced embodiments, the mixture of proteins further comprises at least one growth factor protein. The growth factor protein can include, but is not limited to, fibroblast growth factor-I (FGF-I), FGF-II, FGF-9, leukocyte inhibitory factor (LIF), insulin, insulin growth factor I (IGF-I), IGF-II, platelet-derived growth factor AA (PDGF-AA), PDGF-BB, PDGF-AB, stromal derived factor-2 (SDF-2), pituitary thyroid hormone (PTH), growth hormone, hepatocyte growth factor (HGF), epithelial growth factor (EGF), transforming growth factor-xcex1 (TGFxcex1) and hedgehog proteins. Typically, the growth factor protein comprises from about 0.01% to about 50% of the mixture of proteins. In one aspect, the growth factor protein comprises from about 0.05% to about 25% of the mixture of proteins; in another aspect, the growth factor protein comprises from about 0.1% to about 10% of the mixture of proteins. Preferably, the growth factor protein is fibroblast growth factor-I (FGF-I). In this aspect, the FGF-I comprises from about 0.001% to about 10% of the mixture of proteins.
In yet another aspect of each of the above-identified embodiments of the present invention, the composition further comprises one or more serum proteins. The serum proteins can include, but are not limited to, albumin, transferrin, xcex12-Hs GlycoP, IgG, xcex11-antitrypsin, xcex22-microglobulin, Apo A1 lipoprotein (LP) and Factor XIIIb. In one aspect, the serum proteins are selected from the group consisting of albumin, transferrin, Apo A1 LP and Factor XIIIb.
In one aspect of any of the above-referenced embodiments of the present invention, the mixture of proteins comprises TGFxcex21, TGFxcex22, TGFxcex23, BMP-2, BMP-3, BMP-4, BMxcex25, BMP-6, BMP-7, CDMP, FGF-I, osteocalcin, osteonectin, BSP, lysyloxidase, cathepsin L pre, albumin, transferrin, Apo A1 LP and Factor XIIIb. In another aspect, the mixture of proteins comprises Bone Protein (BP). In yet another aspect, the cartilage inducing composition has an identifying characteristic selected from the group consisting of an ability to induce cellular infiltration, an ability to induce cellular proliferation, an ability to induce angiogenesis, and an ability to induce cellular differentiation to type II collagen-producing chondrocytes.
In one aspect of any of the above-referenced embodiments of the present invention, the cartilage-inducing composition is at a concentration of from about 0.5% to about 33% by weight of the product. In another aspect, the cartilage-inducing composition is at a concentration of from about 1% to about 20% by weight of the product.
In the first embodiment of the product of the present invention, the mixture of proteins, when used at a concentration of at least about 10 xcexcg per 6.5-7.3 mg of bovine tendon collagen in a rat subcutaneous assay, induces a bone score of from about 1.0 to about 3.5, using a bone grading scale set forth in Table 8, and induces a cartilage score of at least about 1.2, using a cartilage grading scale set forth in Table 9.
In the second and third embodiments of the product of the present invention, the composition, when used at a concentration of at least about 10 xcexcg per 6.5-7.3 mg of bovine tendon collagen in a rat subcutaneous assay, induces a bone score of less than about 2.0, using a bone grading scale set forth in Table 8, and induces a cartilage score of at least about 2.0, using a cartilage grading scale set forth in Table 9. Preferably, in the second and third embodiments, the composition, when used at a concentration of at least about 10 xcexcg per 6.5-7.3 mg of bovine tendon collagen in a rat subcutaneous assay, induces a bone score of less than about 2.0, using a bone grading scale set forth in Table 8, and induces a cartilage score of at least about 2.5, using a cartilage grading scale set forth in Table 9. More preferably, in the second and third embodiments, the composition, when used at a concentration of at least about 10 xcexcg per 6.5-7.3 mg of bovine tendon collagen in a rat subcutaneous assay, induces a bone score of less than about 2.0, using a bone grading scale set forth in Table 8, and induces a cartilage score of at least about 3.0, using a cartilage grading scale set forth in Table 9.
In one aspect of the first embodiment of the present invention, the ratio of TGFxcex21 to all other proteins in the mixture of proteins is at least about 1:10; in another aspect, the ratio of TGFxcex21 to all other proteins in the mixture of proteins is at least about 1:3; in another aspect, the ratio of TGFxcex21 to all other proteins in the mixture of proteins is at least about 1:1; in another aspect, the ratio of TGFxcex21 to all other proteins in the mixture of proteins is at least about 10:1.
In the second or third embodiment of the product of the present invention, the TGFxcex2 protein can be a recombinant TGFxcex2 protein, or can be purified from a bone-derived protein mixture. In one aspect, the ratio of the TGFxcex2 protein to the BMP protein is greater than about 100:1; in another aspect, the ratio of the TGFxcex2 protein to the BMP protein is greater than about 1000:1; in another aspect, the ratio of the TGFxcex2 protein to the BMP protein is greater than about 10,000:1.
In the third embodiment referenced above, in a preferred aspect, the TGFxcex2 protein is TGFxcex21. In another preferred aspect of this embodiment, the BMP protein is selected from the group consisting of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9 and CDMP.
Various other aspects of each of the above-identified embodiments of the product of the present invention are described in detail below.
The product of the present invention can also be formulated to include: (a) a cartilage repair matrix; and (b) a cartilage-inducing composition associated with the matrix, which includes cells that have been cultured with the above-described mixture of chondrogenesis-enhancing proteins.
The cartilage repair matrix of a shape and size that conforms to the cartilage defect such that the defect is repaired. As such, the matrix can be configured as a sheet, which is most suitable for repairing cartilage tears, or the matrix can be configured to repair a segmental defect, which can include a tapered shape. The cartilage repair matrix can be formed of any suitable material, including synthetic polymeric material and ground substances. In one embodiment, the matrix is bioresorbable. In another embodiment, the matrix is porous. When the matrix is configured as a sheet, the matrix is preferably not cross-linked, and when the matrix is configured to repair a segmental defect, the matrix is preferably cross-linked.
The cartilage-inducing composition can be associated with the matrix by any suitable method, including, but not limited to freeze-drying the composition onto a surface of said matrix and suspension within said cartilage repair matrix of a delivery formulation containing said composition. Additionally, the composition can be associated with the matrix ex vivo or in vivo.
Another embodiment of the present invention relates to a method for repair of cartilage lesions, which includes the steps of implanting and fixing into a cartilage lesion a cartilage repair product of the present invention, as described above, including a cartilage repair product including an of the above-referenced embodiments of a cartilage-inducing composition. The method of the present invention can be used to enhance the rate and/or quality of repair of vascular cartilage tears and segmental defects, and can provide the ability to repair semivascular and avascular tears and segmental defects that, prior to the present invention, were typically considered to be irreparable. When the lesion is in semivascular or avascular cartilage, the product can additionally include a time controlled delivery formulation.
In one aspect, the method of the present invention includes the use of two cartilage repair products to repair a segmental defect. The first product includes a cartilage repair matrix, which is configured as a sheet, is associated with the chondrogenesis-inducing composition as described above. The second product includes a cartilage repair matrix configured to replace cartilage removed from the segmental defect, which may or may not be associated with the chondrogenesis-inducing composition of the present invention.